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Multicenter Study
. 2025 Mar 25;15(1):10321.
doi: 10.1038/s41598-024-77858-w.

Assessing differential application of thromboprophylaxis regimes related to risk of pulmonary embolism and mortality in COVID-19 patients through instrumental variable analysis

Linda Nab #  1 , Chantal Visser #  2 , Bas C T van Bussel  3   4 , Albertus Beishuizen  5 , Remy H H Bemelmans  6 , Hugo Ten Cate  4   7   8   9 , F Nanne Croles  10 , Coen van Guldener  11 , C Peter C de Jager  12 , Menno V Huisman  13   14 , Marten R Nijziel  15 , Pieter W Kamphuisen  16   17 , Frederikus A Klok  13 , Stephanie C E Koster  18 , Nuray Kuşadasi  19 , Karina Meijer  20 , Corstiaan A den Uil  21   22   23 , Roger E G Schutgens  24 , Frank Stam  25 , Alexander P J Vlaar  26 , Eline A Vlot  27 , Marijke P M Linschoten  28 , Folkert W Asselbergs  29   30 , Marieke J H A Kruip  2 , Saskia le Cessie  1   31 , Suzanne C Cannegieter  32 ; Dutch Covid and Thrombosis Coalition & the CAPACITY-COVID collaborative consortium
Collaborators, Affiliations
Multicenter Study

Assessing differential application of thromboprophylaxis regimes related to risk of pulmonary embolism and mortality in COVID-19 patients through instrumental variable analysis

Linda Nab et al. Sci Rep. .

Abstract

Thrombotic complications are common in Coronavirus disease 2019 (COVID-19) patients, with pulmonary embolism (PE) being the most frequent. Randomised trials have provided inconclusive results on the optimal dosage of thromboprophylaxis in critically ill COVID-19 patients. We utilized data from the multicentre CAPACITY-COVID patient registry to assess the effect of differential application of Low Molecular Weight Heparin (LMWH) dose protocols on PE and in-hospital mortality risk in critically ill COVID-19 patients. An instrumental variable analysis was performed to estimate the intention-to-treat effect, utilizing differences in thromboprophylaxis prescribing behaviour between hospitals. We included 939 patients with PCR confirmed SARS-CoV-2 infection from 34 hospitals. Two-hundred-and-one patients (21%) developed a PE. The adjusted cause-specific HR of PE was 0.92 (95% CI: 0.73-1.16) per doubling of LMWH dose. The adjusted cause-specific HR for in-hospital mortality was 0.82 (95% CI: 0.65-1.02) per doubling of LMWH dose. This dose-response relationship was shown to be non-linear. To conclude, this study did not find evidence for an effect of LMWH dose on the risk of PE, but suggested a non-linear decreased risk of in-hospital mortality for higher doses of LMWH. However, uncertainty remains, and the dose-response relationship between LMWH dose and in-hospital mortality needs further investigation in well-designed studies.

Keywords: COVID-19; Dose–response relationship; Drug; Heparin; Hospital mortality; Low-molecular-weight; Pulmonary embolism.

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Conflict of interest statement

Competing interests: Frederikus A. Klok reports grants or contracts from Bayer, BMS, BSCI, MSD, Leo Pharma, Actelion, Pharm-X, The Netherlands Organisation for Health Research and Development, The Dutch Thrombosis Association, The Dutch Heart Foundation and the Horizon Europe Program, all unrelated to this work and paid to his institution. Karina Meijer has received consulting fees from Uniqure and speaker fees from Alexion, Bayer and CSL Behring paid to her institution. Roger E. G. Schutgens has received unrestricted grants paid to the department for research outside this work from Bayer, CSL Behring, Novartis, NovoNordisk, Octapharma, Roche and Sobi. Alexander P. J. Vlaar has received consulting fees from InflaRx paid to his institution. Folkert W. Asselbergs has received payments from UCL Hospitals NIHR Biomedical Research Centre paid to himself. Marieke J. H. A. Kruip has received unrestricted grants paid to the department for research outside this CSL Behring. The other authors have no relevant financial or non-financial interests to disclose.

Figures

Fig. 1
Fig. 1
Flow diagram of patient selection. Flow diagram of patient selection from the CAPACITY-COVID registry (HDU, high dependency unit, ICU, intensive care unit).
Fig. 2
Fig. 2
Number of PE diagnoses and number of hospitalised patients. The number of PE diagnoses (black line) and the number of patients hospitalised at the high dependency unit (HDU) or intensive care unit (ICU) (grey line) per week. A thromboprophylaxis guidance document was published in the Netherlands on 16 April 2020 (week 7, dashed line).
Fig. 3
Fig. 3
Cumulative incidence for PE. Cumulative incidence for PE in a competing risk analysis adjusted for the competing risk of in-hospital mortality and transfer to another hospital for the tertiles of LMWH dose (panels A–C). To account for the competing risk of hospital discharge, end of follow-up of discharged patients was censored at the date of observing the last event in the data (13 July 2020, > 49 days).
Fig. 4
Fig. 4
Cumulative incidence for in-hospital mortality. Cumulative incidence for in-hospital mortality in a competing risk analysis adjusted for the competing risk of transfer to another hospital for the tertiles of LMWH dose (panels A-C). To account for the competing risk of hospital discharge, end of follow-up of discharged patients was censored at the date of observing the last event in the data (13 July 2020, > 49 days).
Fig. 5
Fig. 5
Relationship between protocolised LMWH dose and PE. Relationship between protocolised LMWH dose and PE analysed with a restricted cubic spline with 4 knots in a cause-specific Cox proportional hazard model. The knots were placed at 2,850, 3,971, 5,700 and 11,400 IE anti-Xa. (A) Crude model; (B) model adjusted for calendar time (days between 27 February 2020 and HDU/ICU admission), age, hospital transfer and weight. To account for the competing risk of hospital discharge, end of follow-up of discharged patients was censored at the date of observing the last event in the data (13 July 2020, > 49 days).
Fig. 6
Fig. 6
Relationship between protocolised LMWH dose and in-hospital mortality. Relationship between protocolised LMWH dose and in-hospital mortality analysed with a cubic restricted spline with 4 knots in a cause-specific Cox proportional hazard model. The knots were placed at 2,850, 3,971, 5,700 and 11,400 IE anti-Xa. (A) Crude model; (B) model adjusted for calendar time (days between 27 February 2020), age, hospital transfer and weight. To account for the competing risk of hospital discharge, end of follow-up of discharged patients was censored at the date of observing the last event in the data (13 July 2020, > 49 days).
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References

    1. Klok, F. A. et al. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thromb. Res.191, 145–147 (2020). - PMC - PubMed
    1. Llitjos, J. F. et al. High incidence of venous thromboembolic events in anticoagulated severe COVID-19 patients. J. Thromb. Haemost.18, 1743–1746. 10.1111/jth.14869 (2020). - PMC - PubMed
    1. Lodigiani, C. et al. Venous and arterial thromboembolic complications in COVID-19 patients admitted to an academic hospital in Milan, Italy. Thromb. Res.191, 9–14 (2020). - PMC - PubMed
    1. Middeldorp, S. et al. Incidence of venous thromboembolism in hospitalized patients with COVID-19. J. Thromb. Haemost.18, 1995–2002 (2020). - PMC - PubMed
    1. Malas, M. B. et al. Thromboembolism risk of COVID-19 is high and associated with a higher risk of mortality: A systematic review and meta-analysis. EClinicalMedicine29, 100639 (2020). - PMC - PubMed

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